Dr. matthias krause - actin cytoskeleton regulation at the intersection of endocytosis, wnt signalling, and cell migration

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**Matthias Krause** ------------------- King's College London, UK ### **Actin cytoskeleton regulation at the intersection of endocytosis, Wnt signalling, and cell migration** How cells internalise surface receptors controls everything from embryonic development to tissue maintenance, yet the molecular machinery driving this remains incompletely understood. Canonical Wnt signalling is essential for both, and while Wnt receptor internalisation is required for pathway activation, how this uptake occurs has been controversial. Two endocytic routes exist: classical Clathrin-Mediated Endocytosis (CME), and the more recently discovered Fast Endophilin-Mediated Endocytosis (FEME) — a rapid, clathrin-independent mechanism operating at the leading edge of migrating cells. In the first of two stories, we show that Wnt3a simultaneously triggers both CME and FEME of Wnt receptors, even at low ligand concentrations sufficient for pathway activation, resolving previous controversies. This efficient endocytosis is specifically facilitated by the actin regulator Mena — identifying it as a key and unexpected mediator of Wnt receptor complex internalisation and Wnt activation. In a second story, we address how actin dynamics are regulated during FEME itself — a question that has remained open since the pathway was discovered. NHSL1, a Nance-Horan Syndrome protein family member, controls cell protrusions and migration, but also localises to vesicular compartments where its function has been unknown. We show that NHSL1 and its uncharacterised family member NHSL2 cooperate with endophilin A2 and